Extensive research supports a dominant role of mammalian prefrontal cortex (PFCx) in the selection of sensory stimuli and in control of goal directed behavior. Behavioral and physiological studies reveal an inhibitory PFCx output to diverse neural systems with PFCx regions functioning to both filter irrelevant sensory inputs and to inhibit inappropriate behavior. In non-human primates with PFCx ablation, distractibility due to intrusion of irrelevant neural inputs produces an inability to maintain focused attention with subsequent deterioration of behavioral performance. Although observation of patients supports a similar role of human PFCx in the control of attention allocation, little information on the underlying physiological mechanisms is available. It is proposed that, as in animals, inability to control early stages of sensory processing coupled with abnormalities in the maintenence of attention and orientation systems are the basis of the disorganized behavior apparent after human PFCx damage. Recent studies of auditory event-related potentials (ERPs) from our laboratory confirm abnormalities in both attention and orientation capacity in humans with PFCx damage. Experiments are proposed to further define these deficits and to study the parallel phenomena in the somatosensory and visual modalities. If PFCx is a critical supramodal region, lesions of this area should produce deficits in the selection of sensory information associated with attention and orientation abnormalities irrespective of the sensory modality. To address this issue, experiments on PFCx lesioned humans are proposed in the auditory, visual and somatosensory modalities to test three interrelated hypothesis: 1) is there a deficit in the control of sensory inputs as manifested by abnormal increases in amplitude of sensory evoked potentials?, 2) are there hemispheric aysmmetries in attention mechanisms as revealed by decrements in the negative electrical shift generated to selectively attended inputs?, and 3) is there evidence of a decreased orienting response to novel inputs as indexed by a decrement in the N200-P300 complex generated to unexpected and deviant stimuli? These studies may provide insight into the contribution of human PFCx to the control of stimulus selection, orientation and attention systems employing non-invasive techniques and may permit more objective evaluation of prefrontal function in neurological and psychiatric populations.